Elsevier

Antiviral Research

Volume 64, Issue 3, December 2004, Pages 145-160
Antiviral Research

Review
Crimean–Congo hemorrhagic fever

https://doi.org/10.1016/j.antiviral.2004.08.001Get rights and content

Abstract

Crimean–Congo hemorrhagic fever (CCHF) is a tick-borne disease caused by the arbovirus Crimean–Congo hemorrhagic fever virus (CCHFV), which is a member of the Nairovirus genus (family Bunyaviridae). CCHF was first recognized during a large outbreak among agricultural workers in the mid-1940s in the Crimean peninsula. The disease now occurs sporadically throughout much of Africa, Asia, and Europe and results in an approximately 30% fatality rate. After a short incubation period, CCHF is characterized by a sudden onset of high fever, chills, severe headache, dizziness, back, and abdominal pains. Additional symptoms can include nausea, vomiting, diarrhea, neuropsychiatric, and cardiovascular changes. In severe cases, hemorrhagic manifestations, ranging from petechiae to large areas of ecchymosis, develop. Numerous genera of ixodid ticks serve both as vector and reservoir for CCHFV; however, ticks in the genus Hyalomma are particularly important to the ecology of this virus. In fact, occurrence of CCHF closely approximates the known world distribution of Hyalomma spp. ticks. Therefore, exposure to these ticks represents a major risk factor for contracting disease; however, other important risk factors are known and are discussed in this review. In recent years, major advances in the molecular detection of CCHFV, particularly the use of real-time reverse transcription-polymerase chain reaction (RT-PCR), in clinical and tick samples have allowed for both rapid diagnosis of disease and molecular epidemiology studies. Treatment options for CCHF are limited. Immunotherapy and ribavirin have been tried with varying degrees of success during sporadic outbreaks of disease, but no case-controlled trials have been conducted. Consequently, there is currently no antiviral treatment for CCHF approved by the U.S. Food and Drug Administration (FDA). However, renewed interested in CCHFV, as well as increased knowledge of its basic biology, may lead to improved therapies in the future. This article reviews the history, epidemiology, ecology, clinical features, pathogenesis, diagnosis, and treatment of CCHF. In addition, recent advances in the molecular biology of CCHFV are presented, and issues related to its possible use as a bioterrorism agent are discussed.

Section snippets

Early history of Crimean–Congo hemorrhagic fever (CCHF)

A disease now considered to be CCHF was described by a physician in the 12th century from the region that is presently Tadzhikistan. The description was of a hemorrhagic disease with the presence of blood in the urine, rectum, gums, vomitus, sputum, and abdominal cavity and was said to be caused by a louse or tick, which normally parasitizes a blackbird (Hoogstraal, 1979). The arthropod described may well have been a species of Hyalomma tick larvae which are frequently found on blackbirds. CCHF

Classification of the virus

CCHFV is a member of the Nairovirus genus of the family Bunyaviridae. Other genera within the family include Orthobunyavirus, Hantavirus, Phlebovirus, and Tospovirus. According to the most recent report from the International Committee on the Taxonomy of Viruses, there are seven recognized species in the genus Nairovirus containing 34 viral strains (Elliott et al., 2000), all of which are believed to be transmitted by either ixodid or argasid ticks (i.e., hard or soft ticks, respectively). The

Structure and molecular biology of the virus

Relatively few studies have been made on the structure of CCHFV. Murphy et al., 1968, Murphy et al., 1973 first described the morphology of CCHFV in the brains of infected newborn mice and noted the similarity to members of the Bunyaviridae family. Indeed, it is now known that CCHFV, and nairoviruses in general, are typical of other members of the family Bunyaviridae in terms of their basic structure, morphogenesis, replication cycle, and physicochemical properties (Donets et al., 1977, Ellis

Strain variation and phylogenetic relationships

Many early studies, based on serological testing, suggested that there are very few significant differences among strains of CCHFV. For example, studies employing modified agar gel diffusion precipitation, neutralization, cell culture interference, and complement fixation tests demonstrated that there were no apparent antigenic differences among strains from several different geographic locations in the former Soviet Union and Africa (Casals, 1969, Casals et al., 1970, Chumakov et al., 1969,

Vertebrate reservoir hosts

Like other tick-borne zoonotic agents, CCHFV generally circulates in nature unnoticed in an enzootic tick–vertebrate–tick cycle. CCHFV has been isolated from numerous domestic and wild vertebrates, including cattle and goats (Woodall et al., 1965, Causey et al., 1970), sheep (Yu-Chen et al., 1985), hares (Chumakov, 1974), hedgehogs (Causey et al., 1970), a Mastomys spp. mouse (Saluzzo et al., 1985), and even domestic dogs (Shepherd et al., 1987a, Shepherd et al., 1987b). Sera from several

Clinical features

Humans appear to be the only host of CCHFV in which disease is manifested (except for newborn mice). In contrast to the inapparent infection in most other vertebrate hosts, human infection with CCHFV often results in severe hemorrhagic disease. The historical accounts of disease attributed to CCHF have been reviewed in detail by Hoogstraal (1979). The typical course of CCHF has been noted by some authors as progressing through four distinct phases, i.e., incubation, prehemorrhagic, hemorrhagic,

Pathogenesis/clinical pathology

The pathogenesis of CCHF is poorly understood. Because CCHF occurs sporadically, and in areas where clinical pathology facilities are limited, complete autopsies are seldom performed on patients who die from the disease. Additional factors that hamper studies on CCHF include the need for specialized laboratories (i.e., biosafety level-4 (BSL-4) containment) and lack of available animal models of disease. Therefore, limited knowledge of pathogenesis is often obtained from blood changes and liver

Diagnosis

Early diagnosis is essential, both for the outcome of the patient and, because of the potential for nosocomial infections, to prevent further transmission of disease. Clinical symptoms and patient history, especially travel to endemic areas and history of tick bite or exposure to blood or tissues of livestock or human patients, are the first indicators of CCHF. The differential diagnosis should include rickettsiosis (tick-borne typhus and African tick bite fever), leptospirosis, and borreliosis

Treatment

Treatment options for CCHF are limited. Early remedies included giving rutin (a bioflavonoid compound found in buckwheat), ascorbic acid, and calcium chloride for the treatment of the hemorrhagic syndrome. It was also suggested that with extensive blood loss, transfusions and blood substitutes such as polyglutin, plasma, and hemodes were necessary and intravenous injections of gelatin and aminocaproic acid were also indicated. Much emphasis was also placed on preventing reinfection, including

Risk factors

There are several groups of individuals who are considered to be at-risk of contracting CCHFV. Specifically, people from endemic areas who are susceptible to tick bite, particularly from Hyalomma spp. ticks. These would include individuals who work outdoors, particularly those who work with large domestic animals. Although CCHFV has been isolated from numerous species of ticks (see Section 5), those of the Hyalomma genus are considered the primary vector in CCHF enzootic and endemic areas. The

Potential bioterrorism concerns

The highly pathogenic nature of the CCHFV has led to the fear that it might be used as an agent of bioterrorism and/or biowarfare and has resulted in its inclusion as a CDC/NIAID Category C Priority Pathogen. CCHFV can be transmitted from person to person, has a high case-fatality rate, and may be transmissible by small-particle aerosol; but, its inability to replicate to high concentrations in cell culture is cited as a major impediment to its development as a mass casualty weapon (Borio et

Acknowledgements

I thank Mike Bray (NIH) for many useful discussions regarding this work. I also thank Katheryn Kenyon (USAMRIID), Aysegul Nalca (Southern Research Institute), and Mike Bray (NIH) for critically reading the manuscript and providing useful editorial suggestions. Many thanks go to Christopher Mores (University of Florida) for helpful discussions regarding phylogenetic analyses and to Connie Schmaljohn (USAMRIID) for supplying Fig. 1, Fig. 2. Additionally, the author is indebted to members of the

References (121)

  • S. Mahanty et al.

    Pathogenesis of filoviral hemorrhagic fevers

    Lancet Infect. Dis.

    (2004)
  • K.S. Makarova et al.

    A novel superfamily of predicted cysteine proteases from eukaryotes, viruses and Chlamydia pneumoniae

    TIBS

    (2000)
  • A.C. Marriott et al.

    Comparison of the S RNA segments and nucleoprotein sequences of Crimean–Congo hemorrhagic fever, Hazara, and Dugbe viruses

    Virology

    (1992)
  • T.G. Okorie

    Comparative studies on the vector capacity of the different stages of Ambloyomma variegatum Fabricius and Hyalomma rufipes Koch for Congo virus, after intracoelomic inoculation

    Vet. Parasitol.

    (1991)
  • J. Paragas et al.

    A simple assay for determining antiviral activity against Crimean–Congo hemorrhagic fever virus

    Antiviral Res.

    (2004)
  • P. Pullikotil et al.

    Development of protein-based inhibitors of the proprotein of convertase SKI-1/S1P

    J. Biol. Chem.

    (2004)
  • J.F. Saluzzo et al.

    Crimean–Congo haemorrhagic fever and Rift Valley fever in south-eastern Mauritania

    Lancet

    (1985)
  • A.J. Shepherd et al.

    Field and laboratory investigation of Crimean–Congo haemorrhagic fever virus (Nairovirus, family Bunyaviridae) infection in birds

    Trans. R. Soc. Trop. Med. Hyg.

    (1987)
  • I. Andersson et al.

    Human MxA protein inhibits the replication of Crimean–Congo hemorrhagic fever virus

    J. Virol.

    (2004)
  • I. Andersson et al.

    Role of actin filaments in targeting of Crimean–Congo hemorrhagic fever virus nucleocapsid protein to perinuclear regions of mammalian cells

    J. Med. Virol.

    (2004)
  • M.Y. Balakirev et al.

    Deubiquitinating function of adenovirus proteinase

    J. Virol.

    (2002)
  • Berezin, V.V., Chumakov, M.P., Reshetnikov, I.A., Zgurskaya, G.N., 1971a. Study of the role of birds in the ecology of...
  • V.V. Berezin et al.

    On the problem of natural hosts of Crimean hemorrhagic fever virus in Astrakhan region

    Tr. Inst. Polio Virusn. Entsefalitov Akad. Med. Nauk SSSR

    (1971)
  • D.H. Bishop

    Biology and molecular biology of bunyaviruses

  • L. Borio et al.

    Hemorrhagic fever viruses as biological weapons: medical and public health management

    J. Am. Med. Assoc.

    (2002)
  • M. Bray et al.

    Ebola hemorrhagic fever and septic shock

    J. Infect. Dis.

    (2003)
  • M.I. Burney et al.

    Nosocomial outbreak of viral hemorrhagic fever caused by Crimean hemorrhagic fever–Congo virus in Pakistan

    Am. J. Trop. Med. Hyg.

    (1976)
  • F.J. Burt et al.

    Investigation of tick-borne viruses as pathogens of humans in South Africa and evidence of Dugbe virus infection in a patient with prolonged thrombocytopenia

    Epidemiol. Infect.

    (1996)
  • A.M. Butenko et al.

    Isolation and investigation of Astrakhan strain (“Drozdov”) of Crimean hemorrhagic fever virus and data on serodiagnosis of this infection

    Mater. 15 Nauchn. Sess. Inst. Polio Virus Entsefalitov (Moscow)

    (1968)
  • J.D. Callahan et al.

    Development and evaluation of serotype- and group-specific fluorogenic reverse transcriptase PCR (TaqMan) assays for dengue virus

    J. Clin. Microbiol.

    (2001)
  • J. Casals

    Antigenic similarity between the virus causing Crimean hemorrhagic fever and Congo virus

    Proc. Soc. Exp. Biol. Med.

    (1969)
  • J. Casals et al.

    A review of Soviet viral hemorrhagic fevers

    J. Infect. Dis.

    (1969)
  • O.R. Causey et al.

    Congo virus from domestic livestock, African hedgehogs, and arthropods in Nigeria

    Am. J. Trop. Med. Hyg.

    (1970)
  • M.P. Chumakov

    A new tick-borne virus disease—Crimean hemorrhagic fever

  • M.P. Chumakov

    A short study of the investigation of the virus of Crimean hemorrhagic fever

    Tr. Inst. Polio Virusn. Entsefalitov Akad. Med. Nauk SSSR

    (1965)
  • M.P. Chumakov

    A new virus disease—Crimean hemorrhagic fever

    Nov. Med.

    (1947)
  • M.P. Chumakov

    Some results of investigation of the etiology and immunology of Crimean hemorrhagic fever

    Tr. Inst. Polio Virusn. Entsefalitov Akad. Med. Nauk SSSR

    (1971)
  • M.P. Chumakov

    Investigations of arboviruses in the USSR and the question of possible association through migratory birds between natural arbovirus infection foci in the USSR and warm-climate countries

  • M.P. Chumakov

    On 30 years of investigation of Crimean hemorrhagic fever

    Tr. Inst. Polio Virusn. Entsefalitov Akad. Med. Nauk SSSR

    (1974)
  • M.P. Chumakov et al.

    New data on the virus causing Crimean hemorrhagic fever (CHF)

    Vopr. Virusol.

    (1968)
  • M.P. Chumakov et al.

    Proofs of etiological identity to Crimean hemorrhagic fever in Central Asian hemorrhagic fever

  • M.P. Chumakov et al.

    Antigenic relationships between the Soviet strains of Crimean hemorrhagic fever virus and the Afro-Asian Congo virus strains

    Mater. 16 Nauchn. Sess. Inst. Polio Virus Entsefalitov (Moscow)

    (1969)
  • C.M. Clerex-van Haaster et al.

    The 3′ terminal RNA sequences of bunyaviruses and nairoviruses (Bunyaviridae): evidence of end sequence generic differences within the virus family

    J. Gen. Virol.

    (1982)
  • D.L. Dickson et al.

    Replication and tissue tropisms of Crimean–Congo hemorrhagic fever virus in experimentally infected adult Hyalomma truncatum (Acari: Ixodidae)

    J. Med. Entomol.

    (1992)
  • D.J. Dohm et al.

    Transmission of Crimean–Congo hemorrhagic fever virus by Hyalomma impeltatum (Acari: Ixodidae) after experimental infection

    J. Med. Entomol.

    (1996)
  • M.W. Dols

    The Black Death in the Middle East

    (1977)
  • M.A. Donets et al.

    Physicochemical characteristics, morphology and morphogenesis of virions of the causative agent of Crimean hemorrhagic fever

    Interviology

    (1977)
  • M.A. Donets et al.

    Immunosorbent assays for diagnosis of Crimean–Congo haemorrhagic fever (CCHF)

    Am. J. Trop. Med. Hyg.

    (1982)
  • C. Drosten et al.

    Rapid detection and quantification of RNA of Ebola and Marburg viruses, Lassa virus, Crimean–Congo hemorrhagic fever virus, Rift Valley fever virus, dengue virus, and yellow fever virus by real-time reverse transcription-PCR

    J. Clin. Microbiol.

    (2002)
  • C. Drosten et al.

    Crimean–Congo hemorrhagic fever in Kosovo

    J. Clin. Microbiol.

    (2002)
  • Cited by (705)

    View all citing articles on Scopus
    1

    The views, opinions, and findings contained herein are those of the author and should not be construed as an official Department of the Army position, policy, or decision unless so designated by other documentation.

    View full text